Relative toxicity and tumor-promoting ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) in hairless mice.
2,3,7,8-Tetrachlorodibenzo-p-dixoin 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are highly toxic members of a class of environmental contaminants, the polychlorinated aromatic hydrocarbons (PCAH), which exhibit a similar and highly characteristic spectrum of toxic effects. For purposes of risk assessment, it is important to be able to make accurate estimates of the relative potency of these and related compounds. Previous investigations have indicated that, in acute exposure or in vitro studies, PCDF is approximately 0.1 times as toxic and HCDF is approximately 0.01 times as toxic as TCDD. In this study, we compared the relative toxicity and tumor-promoting abilities of TCDD, PCDF, and HCDF in hairless mouse skin. Female hairless mice (HRS/J hr/hr) were treated dermally with the initiator MNNG, then dosed twice weekly for 20 weeks with acetone, TCDD (2.5-10 ng/mouse/dose), PCDF (25-100 ng/mouse/dose), or HCDF (250-1000 ng/mouse/dose) as promoter. TCDD, PCDF, and HCDF were all potent promoters for the induction of squamous cell papillomas. There was, however, no difference in the incidence or multiplicity of papilloma formation between groups. The same doses of the three PCAH, in the absence of initiator, induced no skin papillomas. TCDD produced a significant increase in liver:body weight ratio (p less than 0.001) at all doses and a decrease in thymus:body weight ratio at a dose of 10 ng (p less than 0.001). Mice treated with PCDF and HCDF had marked thymic and splenic involution, liver hypertrophy, mucous cell hyperplasia in the fundic portion of the glandular stomach, and loss of body weight. PCDF and HCDF produced a greater incidence and severity of dermatotoxic effects than TCDD. Based on data for dermal toxicity and changes in body weight and organ weights, PCDF is estimated to be 0.2 to 0.4 times, and HCDF 0.08 to 0.16 times, as toxic as TCDD following repeated dermal exposure. Therefore, toxic equivalence factors generated using data from acute and/or in vitro studies may underestimate the risk from repeated low-dose exposures to these compounds.
Hébert
C D
CD
Experimental Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Harris
M W
MW
Elwell
M R
MR
Birnbaum
L S
LS
D000818:Animals; D001572:Benzofurans / Q000032:analysis / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000473:pathology; D004147:Dioxins / Q000633:toxicity*; D005260:Female; D006984:Hypertrophy; D008099:Liver / Q000032:analysis / Q000473:pathology; D051379:Mice; D008812:Mice, Hairless; D010212:Papilloma / Q000139:chemically induced / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000032:analysis / Q000633:toxicity*; D012867:Skin / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology
D001572:Benzofurans; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; C051412:1,2,3,4,7,8-hexachlorodibenzofuran; C038890:2,3,4,7,8-pentachlorodibenzofuran